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Biophysical Reviews

, Volume 10, Issue 2, pp 517–525 | Cite as

Formation and properties of amyloid fibrils of prion protein

  • Kei-ichi Yamaguchi
  • Kazuo Kuwata
Review

Abstract

Amyloid fibrils formed from prion protein (PrP) are associated with prion diseases. In this review we discuss a number of extrinsic and intrinsic experimental factors related to the formation of PrP amyloid fibrils in vitro. We first examined the effects of ultrasonic power on the induction of amyloid fibrillation from PrP. The most important conclusion drawn from the results is that an applied ultrasonic power of approximately 2 W enhanced the nucleation of amyloid fibrils efficiently but that more powerful ultrasonication led to retardation of growth. We also reviewed evidence on the amyloidogenic regions of PrP based on peptide screening throughout the polypeptide sequence. These results showed that helix 2 (H2) peptides of PrP were capable of both the fibrillation and propagation of straight, long fibrils. Moreover, the conformation of preformed H2 fibrils changed reversibly depending on the pH of the solution, implying that interactions between side-chains modulated the conformation of amyloid fibrils. The evidence discussed in this review relates specifically to PrP but may be relevant to other amyloidogenic proteins.

Keywords

Amyloid fibrils Prion diseases Ultrasonication Amyloidogenic region Conformational change of amyloid fibrils 

Notes

Acknowledgements

We thank Miki Horii and Sachie Hori for providing technical help. K.K. was supported in part by the grant for XFEL key technology and the X-ray Free Electron Lase Priority Strategy Program, Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and grants from the Ministry of Health, Labor and Welfare. The study was also supported by a grant from the Practical Research Project for Rare/Intractable Disease of the Japan Agency for Medical Research Development (AMED).

Compliance with ethical standards

Conflict of interest

Kei-ichi Yamaguchi declares that he has no conflict of interest. Kazuo Kuwata declares that he has no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

References

  1. Adachi M, So M, Sakurai K, Kardos J, Goto Y (2015) Supersaturation-limited and unlimited phase transitions compete to produce the pathway complexity in amyloid fibrillation. J Biol Chem 290:18134–18145CrossRefPubMedPubMedCentralGoogle Scholar
  2. Adrover M, Pauwels K, Prigent S, de Chiara C, Xu Z, Chapuis C, Pastore A, Rezaei H (2010) Prion fibrillization is mediated by a native structural element that comprises helices H2 and H3. J Biol Chem 285:21004–21012CrossRefPubMedPubMedCentralGoogle Scholar
  3. Aguzzi A, Polymenidou M (2004) Mammalian prion biology: one century of evolving concepts. Cell 116:313–327CrossRefPubMedGoogle Scholar
  4. Atarashi R, Satoh K, Sano K, Fuse T, Yamaguchi N, Ishibashi D, Matsubara T, Nakagaki T, Yamanaka H, Shirabe S et al (2011) Ultrasensitive human prion detection in cerebrospinal fluid by real-time quaking-induced conversion. Nat Med 17:175–178CrossRefPubMedGoogle Scholar
  5. Baskakov IV, Aagaard C, Mehlhorn I, Wille H, Groth D, Baldwin MA, Prusiner SB, Cohen FE (2000) Self-assembly of recombinant prion protein of 106 residues. Biochemistry 39:2792–2804CrossRefPubMedGoogle Scholar
  6. Bocharova OV, Breydo L, Parfenov AS, Salnikov VV, Baskakov IV (2005) In vitro conversion of full-length mammalian prion protein produces amyloid form with physical properties of PrPSc. J Mol Biol 346:645–659CrossRefPubMedGoogle Scholar
  7. Bocharova OV, Makarava N, Breydo L, Anderson M, Salnikov VV, Baskakov IV (2006) Annealing prion protein amyloid fibrils at high temperature results in extension of a proteinase K-resistant core. J Biol Chem 281:2373–2379CrossRefPubMedGoogle Scholar
  8. Castilla J, Saa P, Hetz C, Soto C (2005) In vitro generation of infectious scrapie prions. Cell 121:195–206CrossRefPubMedGoogle Scholar
  9. Chapman MR, Robinson LS, Pinkner JS, Roth R, Heuser J, Hammar M, Normark S, Hultgren SJ (2002) Role of Escherichia coli curli operons in directing amyloid fiber formation. Science 295:851–855Google Scholar
  10. Chatani E, Kato M, Kawai T, Naiki H, Goto Y (2005) Main-chain dominated amyloid structures demonstrated by the effect of high pressure. J Mol Biol 352:941–951CrossRefPubMedGoogle Scholar
  11. Chen J, Yagi H, Sormanni P, Vendruscolo M, Makabe K, Nakamura T, Goto Y, Kuwajima K (2012) Fibrillogenic propensity of the GroEL apical domain. Protein Sci 21:102–102CrossRefGoogle Scholar
  12. Chiti F, Stefani M, Taddei N, Ramponi G, Dobson CM (2003) Rationalization of the effects of mutations on peptide and protein aggregation rates. Nature 424:805–808CrossRefPubMedGoogle Scholar
  13. Ciryam P, Tartaglia GG, Morimoto RI, Dobson CM, Vendruscolo M (2013) Widespread aggregation and neurodegenerative diseases are associated with supersaturated proteins. Cell Rep 5:781–790CrossRefPubMedGoogle Scholar
  14. Cobb NJ, Sonnichsen FD, McHaourab H, Surewicz WK (2007) Molecular architecture of human prion protein amyloid: a parallel, in-register beta-structure. Proc Natl Acad Sci USA 104:18946–18951CrossRefPubMedPubMedCentralGoogle Scholar
  15. Collinge J, Sidle KCL, Meads J, Ironside J, Hill AF (1996) Molecular analysis of prion strain variation and the aetiology of 'new variant' CJD. Nature 383:685–690CrossRefPubMedGoogle Scholar
  16. Concha-Marambio L, Pritzkow S, Moda F, Tagliavini F, Ironside JW, Schulz PE, Soto C (2016). Detection of prions in blood from patients with variant Creutzfeldt–Jakob disease. Sci Transl Med 8(370):370ra183Google Scholar
  17. Dobson CM (2003) Protein folding and misfolding. Nature 426:884–890CrossRefPubMedGoogle Scholar
  18. Eisenberg DS, Sawaya MR (2017) Structural studies of amyloid proteins at the molecular level. Annu Rev Biochem 86:69–95CrossRefPubMedGoogle Scholar
  19. Fernandez-Escamilla AM, Rousseau F, Schymkowitz J, Serrano L (2004) Prediction of sequence-dependent and mutational effects on the aggregation of peptides and proteins. Nat Biotechnol 22:1302–1306CrossRefPubMedGoogle Scholar
  20. Fitzpatrick AWP, Falcon B, He S, Murzin AG, Murshudov G, Garringer HJ, Crowther RA, Ghetti B, Goedert M, Scheres SHW (2017) Cryo-EM structures of tau filaments from Alzheimer's disease. Nature 547:185–190CrossRefPubMedPubMedCentralGoogle Scholar
  21. Gasset M, Baldwin MA, Lloyd DH, Gabriel JM, Holtzman DM, Cohen F, Fletterick R, Prusiner SB (1992) Predicted alpha-helical regions of the prion protein when synthesized as peptides form amyloid. Proc Natl Acad Sci USA 89:10940–10944CrossRefPubMedPubMedCentralGoogle Scholar
  22. Govaerts C, Wille H, Prusiner SB, Cohen FE (2004) Evidence for assembly of prions with left-handed beta-helices into trimers. Proc Natl Acad Sci USA 101:8342–8347CrossRefPubMedPubMedCentralGoogle Scholar
  23. Honda RP, Yamaguchi K, Kuwata K (2014) Acid-induced molten globule state of a prion protein CRUCIAL ROLE OF STRAND 1-HELIX 1-STRAND 2 SEGMENT. J Biol Chem 289:30355–30363CrossRefPubMedPubMedCentralGoogle Scholar
  24. Honda RP, Xu M, Yamaguchi K, Roder H, Kuwata K (2015) A native-like intermediate serves as a branching point between the folding and aggregation pathways of the mouse prion protein. Structure 23:1735–1742CrossRefPubMedPubMedCentralGoogle Scholar
  25. Jones EM, Surewicz WK (2005) Fibril conformation as the basis of species- and strain-dependent seeding specificity of mammalian prion amyloids. Cell 121:63–72CrossRefPubMedGoogle Scholar
  26. Kameda H, Usugi S, Kobayashi M, Fukui N, Lee S, Hongo K, Mizobata T, Sekiguchi Y, Masaki Y, Kobayashi A et al (2017) Common structural features of toxic intermediates from alpha-synuclein and GroES fibrillogenesis detected using cryogenic coherent X-ray diffraction imaging. J Biochem 161:55–65CrossRefPubMedGoogle Scholar
  27. Kay LE, Korzhnev DM, Salvatella X, Vendruscolo M, Di Nardo AA, Davidson AR, Dobson CM (2004) Low-populated folding intermediates of Fyn SH3 characterized by relaxation dispersion NMR. Nature 430:586–590CrossRefPubMedGoogle Scholar
  28. Kimura T, Sakamoto T, Leveque JM, Sohmiya H, Fujita M, Ikeda S, Ando T (1996) Standardization of ultrasonic power for sonochemical reaction. Ultrason Sonochem 3:S157–S161CrossRefGoogle Scholar
  29. Kirby L, Birkett CR, Rudyk H, Gilbert IH, Hope J (2003) In vitro cell-free conversion of bacterial recombinant PrP to Prp(res) as a model for conversion. J Gen Virol 84:1013–1020CrossRefPubMedGoogle Scholar
  30. Knowles TP, Fitzpatrick AW, Meehan S, Mott HR, Vendruscolo M, Dobson CM, Welland ME (2007) Role of intermolecular forces in defining material properties of protein nanofibrils. Science 318:1900–1903CrossRefPubMedGoogle Scholar
  31. Koda S, Kimura T, Kondo T, Mitome H (2003) A standard method to calibrate sonochemical efficiency of an individual reaction system. Ultrason Sonochem 10:149–156CrossRefPubMedGoogle Scholar
  32. Kurouski D, Dukor RK, Lu X, Nafie LA, Lednev IK (2012) Spontaneous inter-conversion of insulin fibril chirality. Chem Commun (Camb) 48:2837–2839CrossRefGoogle Scholar
  33. Kuwata K, Li H, Yamada H, Legname G, Prusiner SB, Akasaka K, James TL (2002) Locally disordered conformer of the hamster prion protein: a crucial intermediate to PrPSc? Biochemistry-Us 41:12277–12283CrossRefGoogle Scholar
  34. Kuwata K, Matumoto T, Cheng H, Nagayama K, James TL, Roder H (2003) NMR-detected hydrogen exchange and molecular dynamics simulations provide structural insight into fibril formation of prion protein fragment 106-126. Proc Natl Acad Sci USA 100:14790–14795CrossRefPubMedPubMedCentralGoogle Scholar
  35. Kuwata K, Kamatari YO, Akasaka K, James TL (2004) Slow conformational dynamics in the hamster prion protein. Biochemistry 43:4439–4446Google Scholar
  36. Kuwata K, Nishida N, Matsumoto T, Kamatari YO, Hosokawa-Muto J, Kodama K, Nakamura HK, Kimura K, Kawasaki M, Takakura Y et al (2007) Hot spots in prion protein for pathogenic conversion. Proc Natl Acad Sci USA 104:11921–11926CrossRefPubMedPubMedCentralGoogle Scholar
  37. Kyte J, Doolittle RF (1982) A simple method for displaying the hydropathic character of a protein. J Mol Biol 157:105–132CrossRefPubMedGoogle Scholar
  38. Legname G, Baskakov IV, Nguyen HO, Riesner D, Cohen FE, DeArmond SJ, Prusiner SB (2004) Synthetic mammalian prions. Science 305:673–676CrossRefPubMedGoogle Scholar
  39. Li J, Browning S, Mahal SP, Oelschlegel AM, Weissmann C (2010) Darwinian evolution of prions in cell culture. Science 327:869–872CrossRefPubMedGoogle Scholar
  40. Lopez de la Paz M, Goldie K, Zurdo J, Lacroix E, Dobson CM, Hoenger A, Serrano L (2002) De novo designed peptide-based amyloid fibrils. Proc Natl Acad Sci USA 99:16052–16057CrossRefPubMedPubMedCentralGoogle Scholar
  41. Lu XJ, Wintrode PL, Surewicz WK (2007) Beta-sheet core of human prion protein amyloid fibrils as determined by hydrogen/deuterium exchange. P Natl Acad Sci USA 104:1510–1515CrossRefGoogle Scholar
  42. Makarava N, Ostapchenko VG, Savtchenko R, Baskakov IV (2009) Conformational switching within individual amyloid fibrils. J Biol Chem 284:14386–14395CrossRefPubMedPubMedCentralGoogle Scholar
  43. Mathiason CK, Powers JG, Dahmes SJ, Osborn DA, Miller KV, Warren RJ, Mason GL, Hays SA, Hayes-Klug J, Seelig DM et al (2006) Infectious prions in the saliva and blood of deer with chronic wasting disease. Science 314:133–136CrossRefPubMedGoogle Scholar
  44. Moda F, Gambetti P, Notari S, Concha-Marambio L, Catania M, Park KW, Maderna E, Suardi S, Haik S, Brandel JP et al (2014) Prions in the urine of patients with variant Creutzfeldt-Jakob disease. N Engl J Med 371:530–539CrossRefPubMedPubMedCentralGoogle Scholar
  45. Muramoto T, Scott M, Cohen FE, Prusiner SB (1996) Recombinant scrapie-like prion protein of 106 amino acids is soluble. Proc Natl Acad Sci USA 93:15457–15462CrossRefPubMedPubMedCentralGoogle Scholar
  46. Muta H, Lee YH, Kardos J, Lin Y, Yagi H, Goto Y (2014) Supersaturation-limited amyloid fibrillation of insulin revealed by ultrasonication. J Biol Chem 289:18228–18238CrossRefPubMedPubMedCentralGoogle Scholar
  47. Naiki H, Okoshi T, Ozawa D, Yamaguchi I, Hasegawa K (2016) Molecular pathogenesis of human amyloidosis: lessons from beta2 -microglobulin-related amyloidosis. Pathol Int 66:193–201CrossRefPubMedGoogle Scholar
  48. Nakajima K, Ogi H, Adachi K, Noi K, Hirao M, Yagi H, Goto Y (2016) Nucleus factory on cavitation bubble for amyloid beta fibril. Sci Rep 6:22015CrossRefPubMedPubMedCentralGoogle Scholar
  49. Nakajima K, Nishioka D, Hirao M, So M, Goto Y, Ogi H (2017) Drastic acceleration of fibrillation of insulin by transient cavitation bubble. Ultrason Sonochem 36:206–211CrossRefPubMedGoogle Scholar
  50. Natalello A, Prokorov VV, Tagliavini F, Morbin M, Forloni G, Beeg M, Manzoni C, Colombo L, Gobbi M, Salmona M et al (2008) Conformational plasticity of the Gerstmann-Straussler-Scheinker disease peptide as indicated by its multiple aggregation pathways. J Mol Biol 381:1349–1361CrossRefPubMedGoogle Scholar
  51. Nelson R, Sawaya MR, Balbirnie M, Madsen AO, Riekel C, Grothe R, Eisenberg D (2005) Structure of the cross-beta spine of amyloid-like fibrils. Nature 435:773–778CrossRefPubMedPubMedCentralGoogle Scholar
  52. Nguyen JT, Inouye H, Baldwin MA, Fletterick RJ, Cohen FE, Prusiner SB, Kirschner DA (1995) X-ray diffraction of scrapie prion rods and PrP peptides. J Mol Biol 252:412–422CrossRefPubMedGoogle Scholar
  53. Nitani A, Muta H, Adachi M, So M, Sasahara K., Sakurai K, Chatani E, Naoe K, Ogi H, Hall D et al (2017). Heparin-dependent aggregation of hen egg white lysozyme reveals two distinct mechanisms of amyloid fibrillation. J Biol ChemGoogle Scholar
  54. Paravastu AK, Leapman RD, Yau WM, Tycko R (2008) Molecular structural basis for polymorphism in Alzheimer's beta-amyloid fibrils. Proc Natl Acad Sci USA 105:18349–18354CrossRefPubMedPubMedCentralGoogle Scholar
  55. Peoc'h K, Manivet P, Beaudry P, Attane F, Besson G, Hannequin D, Delasnerie-Laupretre N, Laplanche J (2000) Identification of three novel mutations (E196K, V203I, E211Q) in the prion protein gene (PRNP) in inherited prion diseases with Creutzfeldt–Jakob disease phenotype. Hum Mutat 15:482CrossRefPubMedGoogle Scholar
  56. Petkova AT, Leapman RD, Guo Z, Yau WM, Mattson MP, Tycko R (2005) Self-propagating, molecular-level polymorphism in Alzheimer's beta-amyloid fibrils. Science 307:262–265CrossRefPubMedGoogle Scholar
  57. Prusiner SB (1998) Prions. Proc Natl Acad Sci USA 95:13363–13383CrossRefPubMedPubMedCentralGoogle Scholar
  58. Riek R, Eisenberg DS (2016) The activities of amyloids from a structural perspective. Nature 539:227–235CrossRefPubMedGoogle Scholar
  59. Riek R, Hornemann S, Wider G, Billeter M, Glockshuber R, Wuthrich K (1996) NMR structure of the mouse prion protein domain PrP(121-231). Nature 382:180–182CrossRefPubMedGoogle Scholar
  60. Rost B, Sander C, Schneider R (1994) PHD—an automatic mail server for protein secondary structure prediction. Comput Appl Biosci 10:53–60PubMedGoogle Scholar
  61. Rufo CM, Moroz YS, Moroz OV, Stohr J, Smith TA, Hu X, DeGrado WF, Korendovych IV (2014) Short peptides self-assemble to produce catalytic amyloids. Nat Chem 6:303–309CrossRefPubMedPubMedCentralGoogle Scholar
  62. Saborio GP, Permanne B, Soto C (2001) Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding. Nature 411:810–813CrossRefPubMedGoogle Scholar
  63. Salmona M, Malesani P, De Gioia L, Gorla S, Bruschi M, Molinari A, Della Vedova F, Pedrotti B, Marrari MA, Awan T et al (1999) Molecular determinants of the physicochemical properties of a critical prion protein region comprising residues 106–126. Biochem J 342:207–214PubMedPubMedCentralGoogle Scholar
  64. Salvadores N, Shahnawaz M, Scarpini E, Tagliavini F, Soto C (2014) Detection of misfolded Abeta oligomers for sensitive biochemical diagnosis of Alzheimer's disease. Cell Rep 7:261–268CrossRefPubMedGoogle Scholar
  65. Sawaya MR, Sambashivan S, Nelson R, Ivanova MI, Sievers SA, Apostol MI, Thompson MJ, Balbirnie M, Wiltzius JJ, McFarlane HT et al (2007) Atomic structures of amyloid cross-beta spines reveal varied steric zippers. Nature 447:453–457CrossRefPubMedGoogle Scholar
  66. Schmitz M, Cramm M, Llorens F, Muller-Cramm D, Collins S, Atarashi R, Satoh K, Orru CD, Groveman BR, Zafar S et al (2016) The real-time quaking-induced conversion assay for detection of human prion disease and study of other protein misfolding diseases. Nat Protoc 11:2233–2242CrossRefPubMedGoogle Scholar
  67. Smirnovas V, Baron GS, Offerdahl DK, Raymond GJ, Caughey B, Surewicz WK (2011) Structural organization of brain-derived mammalian prions examined by hydrogen–deuterium exchange. Nat Struct Mol Biol 18:504–506CrossRefPubMedPubMedCentralGoogle Scholar
  68. So M, Yagi H, Sakurai K, Ogi H, Naiki H, Goto Y (2011) Ultrasonication-dependent acceleration of amyloid fibril formation. J Mol Biol 412:568–577CrossRefPubMedGoogle Scholar
  69. Stathopulos PB, Scholz GA, Hwang YM, Rumfeldt JAO, Lepock JR, Meiering EM (2004) Sonication of proteins causes formation of aggregates that resemble amyloid. Protein Sci 13:3017–3027CrossRefPubMedPubMedCentralGoogle Scholar
  70. Suslick KS (1986) The site of sonochemical reactions. IEEE Trans Ultrason Ferroelectr Freq Control 33:143–147CrossRefPubMedGoogle Scholar
  71. Tagliavini F, Prelli F, Verga L, Giaccone G, Sarma R, Gorevic P, Ghetti B, Passerini F, Ghibaudi E, Forloni G et al (1993) Synthetic peptides homologous to prion protein residues 106-147 form amyloid-like fibrils in vitro. Proc Natl Acad Sci USA 90:9678–9682CrossRefPubMedPubMedCentralGoogle Scholar
  72. Tanaka M, Chien P, Naber N, Cooke R, Weissman JS (2004) Conformational variations in an infectious protein determine prion strain differences. Nature 428:323–328CrossRefPubMedGoogle Scholar
  73. Trovato A, Chiti F, Maritan A, Seno F (2006) Insight into the structure of amyloid fibrils from the analysis of globular proteins. PLoS Comput Biol 2:e170CrossRefPubMedPubMedCentralGoogle Scholar
  74. Tuttle MD, Comellas G, Nieuwkoop AJ, Covell DJ, Berthold DA, Kloepper KD, Courtney JM, Kim JK, Barclay AM, Kendall A et al (2016) Solid-state NMR structure of a pathogenic fibril of full-length human alpha-synuclein. Nat Struct Mol Biol 23:409–415CrossRefPubMedPubMedCentralGoogle Scholar
  75. Tycko R, Wickner RB (2013) Molecular structures of amyloid and prion fibrils: consensus versus controversy. Acc Chem Res 46:1487–1496CrossRefPubMedPubMedCentralGoogle Scholar
  76. Umemoto A, Yagi H, So M, Goto Y (2014) High-throughput analysis of Ultrasonication-forced amyloid fibrillation reveals the mechanism underlying the large fluctuation in the lag time. J Biol Chem 289:27290–27299CrossRefPubMedPubMedCentralGoogle Scholar
  77. Van Melckebeke H, Wasmer C, Lange A, Ab E, Loquet A, Bockmann A, Meier BH (2010) Atomic-resolution three-dimensional structure of HET-s(218-289) amyloid fibrils by solid-state NMR spectroscopy. J Am Chem Soc 132:13765–13775CrossRefPubMedGoogle Scholar
  78. Walsh I, Seno F, Tosatto SC, Trovato A (2014) PASTA 2.0: an improved server for protein aggregation prediction. Nucleic Acids Res 42:W301–W307CrossRefPubMedPubMedCentralGoogle Scholar
  79. Wang F, Wang X, Yuan CG, Ma J (2010) Generating a prion with bacterially expressed recombinant prion protein. Science 327:1132–1135CrossRefPubMedPubMedCentralGoogle Scholar
  80. Weissmann C (2004) The state of the prion. Nat Rev Microbiol 2:861–871CrossRefPubMedGoogle Scholar
  81. Yagi H, Mizuno A, So M, Hirano M, Adachi M, Akazawa-Ogawa Y, Hagihara Y, Ikenoue T, Lee YH, Kawata Y et al (2015) Ultrasonication-dependent formation and degradation of alpha-synuclein amyloid fibrils. Biochim Biophys Acta 1854:209–217CrossRefPubMedGoogle Scholar
  82. Yamaguchi K, Matsumoto T, Kuwata K (2008) Critical region for amyloid fibril formation of mouse prion protein: unusual amyloidogenic properties of the helix 2 peptide. Biochemistry 47:13242–13251CrossRefPubMedGoogle Scholar
  83. Yamaguchi K, Matsumoto T, Kuwata K (2012) Proper calibration of ultrasonic power enabled the quantitative analysis of the ultrasonication-induced amyloid formation process. Protein Sci 21:38–49CrossRefPubMedGoogle Scholar
  84. Yamaguchi K, Kamatari YO, Fukuoka M, Miyaji R, Kuwata K (2013) Nearly reversible conformational change of amyloid fibrils as revealed by pH-jump experiments. Biochemistry 52:6797–6806CrossRefPubMedGoogle Scholar
  85. Yoshimura Y, Lin YX, Yagi H, Lee YH, Kitayama H, Sakurai K, So M, Ogi H, Naiki H, Goto Y (2012) Distinguishing crystal-like amyloid fibrils and glass-like amorphous aggregates from their kinetics of formation. Proc Natl Acad Sci USA 109:14446–14451CrossRefPubMedPubMedCentralGoogle Scholar

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© International Union for Pure and Applied Biophysics (IUPAB) and Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Institute for Protein ResearchOsaka UniversitySuitaJapan
  2. 2.United Graduate School of Drug Discovery and Medical Information SciencesGifu UniversityGifuJapan
  3. 3.Graduate School of MedicineGifu UniversityGifuJapan

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